Project Summary/Narrative- Project 1- PD-linked Susceptibilities in Myeloid-Cell CNS Infiltration It has been difficult to understand the role of the immune system in the pathobiology of Parkinson?s disease (PD). In post-mortem tissue from PD cases and rodent models, ?-synuclein (?-syn) pathology is accompanied by reactive microgliosis, increased pro-inflammatory cytokine expression (e.g., CCL2, TNF, IFN?), infiltration of peripheral lymphocytes, and IgG deposition surrounding degenerating neurons. Several genes, identified in human genetic and pathological studies, are known to be important in susceptibility to late- onset PD, including ?-syn and LRRK2. LRRK2 becomes highly expressed in myeloid cells recruited to the CNS and can broadly mediate inflammatory responses. Pilot data included show, for the first time, a strong peripheral myeloid cell infiltration into the CNS caused by ?-syn over-expression. Our other recent data show that the pathogenic G2019S-LRRK2 mutation enhances the recruitment of CD68+ pro-inflammatory myeloid cells in response to abnormal ?-syn, whereas LRRK2 knockout reduces these pro-inflammatory responses. We hypothesize that the major contributor of LRRK2 positive pro-inflammatory myeloid cells in the CNS that are induced by abnormal ?-syn come from the periphery and not resident microglia. Further, we hypothesize that LRRK2 kinase activity can regulate the process of pro-inflammatory myeloid cell infiltration to the CNS. This hypothesis can be addressed by the recent development of novel genetic tools, namely the CX3CR1-GFP+/- x CCR2-RFP+/- mice that will be bred with LRRK2 transgenic mice. We envisage that one component of the pathophysiology linking LRRK2 and ?-syn together in late-onset PD may be function in neuroimmunological processes. This project dedicates towards evaluating one aspect of this process (myeloid- cell CNS infiltration), with the notion that the data will provide a foundation for a future P50 application that determines the role of LRRK2+ pro-inflammatory cells in the context of ?-syn aggregation and subsequent neurodegeneration.